Pancreatic cancer is the fourth-most common cause of cancer-related death in the United States. Understanding the genetic abnormalities underlying pancreatic cancer pathogenesis is critical for developing robust clinical assays for early detection, as well as for mechanistic therapeutic strategies. The long term objectives of this study are to identify pathogenetic gene amplifications and deletions in pancreatic cancer, and to functionally characterize the underlying oncogenes and tumor suppressor genes. Array-based comparative genomic hybridization (array CGH) on pancreatic cancer cell lines defined previously unrecognized DNA amplifications and deletions, harboring novel candidate oncogenes and tumor suppressor genes. These studies identified two candidate cancer genes in particular whose altered copy number and expression may contribute to pancreatic cancer: SMURF1, which modulates TGFp signaling, and DKK3, likely involved in WNT signaling. A major goal of this proposal is to characterize the function of SMURF1and DKK3 in pancreatic cancer development and progression through studying tumor growth in cell culture and in mice. A second major goal is to extend array CGH studies to primary pancreatic tumors, thereby discovering additional candidate pancreatic cancer genes. These studies will further knowledge of the role of gene amplification and deletion in pancreatic cancer, in particular in regards to the TGFp and WNT pathways, and may provide new strategies for therapeutic intervention. The specific scientific aims of this proposal are: (1) to characterize the role of gene amplification in the pathogenesis of pancreatic cancer, focusing on SMURF1, a modulator of TGFp signaling;(2) to characterize the role of gene deletion in the development of pancreatic cancer, focusing on DKK3, a potential modulator of WNT signaling;and (3) to identify additional novel DNA amplifications and deletions in pancreatic cancer, by array CGH analysis of primary pancreatic tumors.